2-(4&#39;-chloro-4-biphenylyl)propionic acid

ABSTRACT

2-(4&#39;&#39;-Chloro-4-biphenylyl)propionic acid possessing valuable anti-inflammatory activity. It also exhibits analgesic and antipyretic properties.

United States Patent 1 a 3,821,293. 5'

Adams etal. June 28, 1974 1 2-(4-CHLORO-4-BIPHENYLYL)PROPIONIC 260/592,424/317 AC1!) [51] Int. Cl. C07c 63/00 [58] Field of Search 260/515 A[75] Inventors: Stewart Sanders Adams; Bernard John Armitage; JohnStuart Nicholson, all of Nottingham, References Cited England; AntonioRibera Blancafort, UNITED STATES NTS Madrid, Spain 3,624,142 11/1971Shen et al. 260/515 [73] Assignee: The Boots Company Limited, L

, Nottingham, England Primary Examiner-James A. Patten [22] Filed; Dec.15, 1969 Aztorney, Agent, or Firm-Gordon W. Hueschen [21] Appl. N0.:885,280

a o I e Apphcatmn Data 2-(4-Chl0r0-4-biphenylyl)propionic acidpossessing [63] commualtomm'part of valuable anti-inflammatory activity.It also exhibits anabdndoned' algesic and antipyretic properties.

[52] US. Cl 260/515 A, 260/469, 260/475 SC, 1 Claim, No Drawings [5 7ABSTRACT This application is a continuation-in-part of Ser. No. 425,624,filed Jan. 14th 1965, now abandoned, in which application the presentlyclaimed compound appeared in Example 1, page 13. line 9 and in thespecification at line 20, page 3.

The invention provides the novel compound 2-(4'-chloro-4-biphenylyl)propionic acid.

This compound possesses anti-inflammatory acitivity and is useful forthe treatment of inflammatory conditions. It also possesses analgesicandantipyretic properties and is useful for the treatment of conditionsof pain and pyretic conditions. It is useful for the treatment of thesethree conditions individually or in any combination. A particularlynotable feature of the compound is its long lasting effect, which allowsa relatively constant blood level to be achieved throughout a 24 hourperiod, in contrast to short-acting compounds e.g. 2-(4-isobutylphenyl)-propionic acid where there are wide fluctuations inblood levels over 24 hours.

The compound may conveniently be prepared byreacting an ester of4'-chloro-4-biphenylylacetic acid with diethyl carbonate to give amalonic acid ester, methylating the sodium derivative of this ester,hydro- .lysing the ester, and decarboxylating the resulting acid,

viz.

NaOEt The activity of the compound of the invention has .ventionalpharmaceutical forms for such administration, such as for examplesuppositories with cocoa butbeen determined in experimental animalsusing pharmacological tests which are known to be capable ofcharacterising compounds possessing the therapeutic properties ofaspirin, namely anti-inflammatory, analgesic and antipyretic activity;its long lasting effect has been confirmed by blood level experiments.

The compound of the invention may be administered in the conventionalmanner of aspirin or usual manner for other antiinflammatory, analgesic,and antipyretic agents, for example orally, topically, rectally orparenterally, preferably orally. The optimum dosage rate varies with theroute of administration, but normally lies within the range 0.014-l4.0mg./kg., more usually between 0.35-7.0 mg./kg. The unit dose may varyfrom 1 mg. to lOOOmg. per subject per day; fororal administration thedosage rate is preferably 25-600 mg. per subject per day, optionally individed doses.

In use, the compound of the invention is administered in conventionalformulations and accordingly the invention also provides therapeuticcompositions which comprise the compound of the invention in assot 2ciation with pharmaceutical excipients forthe production of compositionsfor oral, topical, rectal or parenteral administration. Thesecompositions preferably contain 0. 1-90 percentby weight of the compoundof the invention. f

Compositions for oral administration are the preferred compositionsof'the invention; and these are the con entional pharmaceutical formsfor such administration, such as for example tablets, capsules,lozenges, powders, effervescent granules, syrups and aqueous and oilysuspensions. The excipients used in the preparation of thesecompositions are the excipients of the pharmacist's art. Thus in thepreparation of tablets, typical excipients include disintegratingagents, e.g., maize starch and lubricating agents, e.g., magnesiumstearate in the preparation of capsules, standard gelation capsules maybe used containing the active ingredient alone or admixed with adiluent. The liquid compositions may comprise as excipients water andsucrose topr'ovide syrups, water, dispersing agents and suspendingagents, e.g., sodium carboxymethylcellulose to provide aqueoussuspensions, and a non-toxic oil, e.g., a vegetable oil such as arachisoil and a suspending agent to provide oily. suspensions.

Compositions forrectal administration are the conpolyethylene glycols.Lotions may comprise a solution in an aliphatic alcohol with 14 carbonatoms which may contain a small proportion of water.

Compositions for parenteral administration are the conventionalpharmaceutical forms for such administration, for example sterilesuspensions in aqueous or oilymedia or sterile solutions in propyleneglycol.

in some formulations it may be beneficial to use the compound of theinvention in the form of particles of very small size, such as forexample, as obtained by fluid energy milling, e.g., micronizing.

. The invention further provides a method of treating inflammatoryconditions, conditions of pain and pyretic conditions, individually orin any combination, which comprises administering the compound of theinvention, preferably orally. 'Salts, esters, amides and alcoholsderived from the compound of the invention may be used in place of thecompound of the invention as such derivatives appear to be metabolisedby the animal body and be converted in the body into the correspondingacid. a

The product of the present invention may of course be employed incombination with other active anti inflammatory agents, analgesics, andantipyretic agents, or with other drugs, as is already conventional inthe art for other existing anti-inflammatory, analgesic and antipyreticmaterials such as aspirin.

' The following non-limitative examples illustrate the invention.

EXAMPLE 1 Aluminium chloride (14.5 g.) in nitrobenzene ml.) at 10C. wastreated with acetyl chloride (9 ml.)

and 4-chlorobiphenyl (17.69 g.) with stirring. After 5 hours the mixturewas decomposed with ice and hydrochloric acid. Nitrobenzen was steamdistilled and the crystalline residue was collected, washed andrecrystallised from ethanol to give 4-acetyl-4' -chlorobiphenyl m.p. 96103C.

This ketone 17.87 g.), sulphur (4 g.) and morpholine (23 ml.) wererefluxed for 7 hours, diluted with ethanol (25 ml.) and thethiomorpholide which separated was collected and washed with ethanol (50ml.). It was hydrolysed by refluxing with 70 percent ehtanol (140 ml.)and 50 percent sodium hydroxide solution for 8 hours. The alcohol wasdistilled, the residue was diluted with hot water, charcoaled, filteredand acidified with dilute hydrochloric acid. The solid which separatedwas collected, washed and recrystallised from ethyl acetate to give4'-chloro-4-biphenylylacetic acid mp. 158 161C.

(Found: C, 68.15; H, 3.95. C H CIO requires C, 68.1; H, 4.5%).

4-Chloro-4-biphenylylacetic acid, (180 g.) was refluxed overnight withethanol (500 ml.) and concentratedsulphuric acid (50ml. The alcohol wasdistilled and the residue was diluted with water. The ester whichseparated was collected and recrystallised from light (325 ml.) wasadded'at 100C, with stirring to a solution of ethyl4-chloro-4-biphenylylacetate (123 g.), in diethyl carbonate (710 ml.).The mixture was distilled until the still head temperature reached 124C.andthe residue was cooled to 0C. overnight. It was treated with glacialacetic acid (62 ml.) in water (250 ml.), extracted with ether and theether extracts were washed with sodium bicarbonate solution, water andthen dried. The ether was evaporated and the residue was distilled, togive an oil which solidified on cooling in a solid carbondioxide/acetone mixture. It was recrystallised from light petroleum(b.p. 40 60C.) to give ethyl 4'-chloro-4-biphenylylmalonate m.p. 47 49C.

added to a stirred solution of sodium ethoxide (from t 2.5 g. of sodium)in ethanol (100 ml.) followed by 4 methyl iodide 16.5 ml.). The mixturewas refluxed for 2 hours, methyl iodide 10 ml.) was added and themixture was refluxed for a further hour. The alcohol was distilled andthe residue was hydrolysed by refluxing for 5 hours with 2.5N sodiumhydroxide solution 200 ml.) in ethanol 100 ml.). The alcohol wasdistilled, the aqueous residue was acidified, the precipitated malonicacid was collected and decarboxylated at 190C. for 1 hour. The residuewas crystallised from aqueous ethan01 to give2-(4'-chloro-4-biphenylyl)propionic acid m.p. l 176C. (Found: C, 69.5;H, 5.1; Cl, 13.8. C H ClO requires C, 69.2; H, 5.0; Cl, 13.6%).

EXAMPLE 2 Compositions hard gelatin capsules No. 5 hard gelatin capsuleswere prepared each containing the following:

(a) 2-(4-chloro-4-biphenylyl)propionic acid 5 mg. lactose 95 mg. (b)2-(4'-chloro-4-biphcnylyl)propionic acid 5 mg. calcium phosphate 5 mg.maize starch mg. (c) 2-(4-chloro-4-biphenylyl)propionic acid 5 mg.

maize starch lactose equal parts by mg. calcium phosphate weight EXAMPLE3 The following mixture (parts by weight) was formed into tablets inconventional manner, each tablet containing 5 mg. of active ingredient:

2-(4'-chloro-4-biphenylyl)propionic acid 5 maize starch 30 lactose 163stearic acid 1 magnesium stearate 1 In a similar manner, 2-(4-chloro-4-biphenylyl)propionic acid is incorporated into other conventionalcompositions and formulations, taking various conventional forms, andadministered as previously described to give the desirable reliefdescribed, depending upon the physiological abnormality or conditionbeing treated.

We claim:

l. 2-(4-Chloro-4-biphenylyl)propionic acid.

